Conversion of beta-, gamma-, and delta-tocopherol to alpha-tocopherol by aminoalkylation and reduction



Patented Aug. 22, 1950 UNITED STATES PATENT OFFICE CONVERSION OF BETA-,

GAM1\IA-, AND

DELTA-TOCOPHEROL TO ALPHA-TOCOPH- EROL BY AMINOALKYLATION AND RE-DUCTION Jersey No Drawing. Application May 14, 1949, Serial No. 93,429

17 Claims. (01. 260-333) This invention relates to an improvement in thevitamin art, and in particular, to a process for converting anytocopherol other than alpha, such as beta-, gamma-, anddelta-tocopherol, and also the esters of tocopherols other than alpha,into a product having higher vitamin E activity, in particular a highercurative power for sterility in the depleted rat. Delta-tocopherol is anewly discovered natural compound disclosed in Baxter, Stern and Weislerapplication, Serial No. 684,770, filed July 19, 1946, now U. S. Patent2,486,541.

Using the accepted system of numbering carbon atoms, it is known thatalpha-tocopherol has methyl groups in the 5, 7, and 8 positionsBetatocopherol is the same except that the methyl group in the '7position is replaced by a hydrogen atom. Gamma-tocopherol is the sameexcept that the methyl roup in the position is replaced by a hydrogenatom. The best evidence now available indicates that delta-tocopherol isthe same as alpha-tocopherol except that hydrogen atoms are substitutedfor the methyl groups both in the 5 and '7 positions. Graphically, thenon-alpha tocopherols have the following structures:

Delta-tocopherol It is also known that beta-, gamma-, anddeltatocopherol have lower antisterility activity than alpha-tocopherol.In spite of these facts, no one has previously devised a suitable methodfor the conversion to alpha-tocopherol of other tocopherols. Suchconversion would be of importance since tocopherols other thanalpha-tothe esters of tocopherols other than alpha into esters ofalpha-tocopherol can be satisfactorily carried out by my invention.

This invention, therefore, has for its object to provide a procedure forconversion of other tocopherols and the esters thereof into thecorresponding alpha-tocopherol compound. Another object is to introducesubstituent groups wherever the 5, 7, and 8 positions of tocopherols andthe esters thereof are occupied only by hydrogen atoms and thus preparesubstances having higher antisterility activity. A still further objectis to provide an improved procedure for substituting methyl groups forhydrogen atoms in the 5, 7, and 8 positions of tocopherols and theesters thereof, so that these compounds are converted intoalpha-tocopherol or its esters. Another object is to provide new vitaminE intermediates. Still another object is to improve the state of theart. Other objects will appear hereinafter.

These and other objects are accomplished by my invention which includesintroducing substituents into the 5, '7, and/or 8 positions of thetocopherols and the esters thereof.

In the following description I have set forth several of the preferredembodiments of my in-' vention but it to be understood that they aregiven by Way of illustration and not in limitation thereof.

This invention involves the replacement of any aromatic hydrogen atomsin the 5, 7, and/or 8 positions of the tocopherols and the estersthereof by substituents and is accomplished in the case of methylgroups, for instance, by the reaction of the tocopherol compound with anaqueoussolution of formaldehyde (40%) in the paraformaldehyde, may beused to introduce the chloromethyl group. Chloromethyl ether, preparedby introducing hydrogen chlorid gas into a mixture of paraformaldehydeand methanol, may also be used. Similarly, dimethyl formal and hydrogenhalide may be used. Other groups than methyl may be introduced usingother reactants of the type mentioned. Thus, ethyl groups can beintroduced using paraldehyde instead of formaldehyde or diethyl formalinstead of dimethyl formal, or propyl groups may be introduced usingpropionaldehyde. Aryl groups can be introduced using benzaldehyde. It isto be understood that all such reactions which involve introduction or"alkyl, aryl, alkaryl, or aralkyl groups shall be included within thescope of my invention and within the meaning of the term haloalkylationas used herein.

In the chloromethylation of tocopherols I have found that the bestconditions consist of treating a 5-10% ethereal solution of the oilcontaining the tocopherols with a 34 mole excess of aqueous Formalin andconcentrated hydrochloric acid at room temperature. The mixture isstirred vigorously while a small stream of hydrogen chlo-- ride gas isintroduced into the mixture.

In ordinary commercial practice, it is a mixture of tocopherols or theesters thereof which is converted to alpha-tocopherol. Pure beta-,gamma, and delta-tocopherol solutions or the esters thereof can also beconverted to alphatocopherol. Ethyl or propyl groups can be substitutedfor aromatic hydrogen atoms in the 5, '7, and 8 positions in solutionscontaining mixtures of beta-, gamma-, and delta-tocopherol or theiresters as well as in solutions containing the pure substances.

Tocopherol esters may be prepared by reacting tocopherols with an acidhalide, such as acetyl chloride, in the presence of a solvent, such aspyridine. I'ocopherol acetates may also be prepared by reactingtocopherols with acetic anhydride in the presence of a solvent, such aspyridine.

Only the tocopherol nucleus is involved in the conversion of lowertocopherol esters to alphatocopherol esters. The length of the esterchain does not materially affect the reaction.

The Mannich reaction may be used to effect conversion of lowertocopherols to alpha-tocopherol but in lower yields. This reactionconsists in the condensation of ammonia or a primary or secondary aminewith formaldehyde and a compound containing a hydrogen atom ofpronounced activity. The condensation results in the replacement of theactive hydrogen atom by an aminomethyl or substituted aminomethyl group.To introduce the methyl group, the amino or substituted amino group canbe removed by high pressure catalytic hydrogenation. Thus, the lowertocopherols, dissolved in a solvent such as absolute ethyl alcohol, maybe treated with an amine such as piperidine and an aldehyde, such asparaformaldehyde, and a very small amount of concentrated hydrochloricacid to catalyze the reaction. The mixture is refluxed for several hoursto produce a product in Which an alkylene piperidine grouping, such asmethylene piperidine, has replaced any aromatic hydrogen atoms in the 5,'7, and 8 positions. This grouping can be catalytically hydrogenated tothe alkyl grouping, e. g., methyl groups, by heating to 165 C. at 2000pounds per square inch pressure in an atmosphere of hydrogen and thepresence of a catalyst, such as copper chromite.

Acetaldehyde may be substituted for paraformaldehyde in the Mannichreaction to give an ethylene piperidine grouping in place of aromatichydrogen atoms in the 5, '7, and 8 positions. Similarly, the use ofpropionaldehyde would result in propylene piperidine groups in place ofaromatic hydrogen atoms in the 5, 7, and 8 positions. Catalytichydrogenation under the conditions mentioned above would then give therespective ethyl or propyl groups in the 5, 7, and 8 positionspreviously occupied by aromatic hydrogen atoms.

Other hydrocarbon groups are introduced in like manner by simultaneousreaction of low potency tocopherols with other aldehydes and with otheraminating materials including ammonia and ammonium salts, primary aminesand their salts, and secondary amines and their salts, Suitablealdehydes include, besides compounds of the formula (Cl-I20) preferablyemployed including formaldehyde and polymers thereof such asparaformaldehyde and in addition to the alkyl aldehydes and particularlythe lower alkyl aldehydes such as acetaldehyde, propionaldehyde,butyraldehyde and the like, such diverse aldehydes as anisaldehyde,benzaldehyde, phenylacetaldehyde and the like. By means of suchaldehydes together with an aminating material, an amino hydrocarbongroup is introduced on the nucleus of the low potency tocopherols, whichgroup is subsequently reduced to the corresponding hydrocarbon group.

The conversion of low potency tocopherols in this manner is typified bytreatment of gammatocopherol by a process wherein 0.6 part by Weight ofgamma-tocopheral is dissolved in 4 parts by weight of ethyl alcohol andreacted with 0.18 part by weight of piperidine hydrochloride and 0.11part by Weight of paraformaldehyde. Reaction is effected by acidifyingthe solution of tocopherol with hydrochloric acid after addition theretoof the piperidine hydrochloride and the paraformaldehyde and refluxingthe reaction mixture for 2 hours. The addition product resulting fromthe aminoalkylation reaction is thereafter reduced to alpha-tocopherol.

Ammonia or primary or secondary amines are suitably employed butreaction is preferably effected with the salt of such materials, thechlorides and hydrochlorides being eminently suited for practising theinvention. The nature of the salt group does not alfect the course ofthe reaction and any of the well-known salts may be employed.

Primary and secondary alkyl amines suitable for practising the inventioninclude methylamine, dimethylamine, ethylamine, B-hydroxy ethylamine,c-chloro ethylamine, diethylamine, dipropylamine, dibutylamine and thelike. Other suitable primary amines include allylamine, benzylamine,ethylene diamine, tetrahydro-B- naphthylamine, w-amino acetophenone andthe like, and other suitable secondary amines in addition to piperidineand the dialkylamines include dibenzylamine, piperazine methylaniline,tetrahydroiso quinoline, methyl diethylethylene diamine and the like.

When formaldehyde is employed as aqueous Formalin, the reaction can becarried out in aqueous solution, although ordinarily it is desirable toefiect reaction in a suitable organic solvent such as ethyl alcohol,isoamyl alcohol or the like.

5. Any of beta-, gamma-, or'delta-tocopherols or mixtures thereof may betreated with an amine and an aldehyde in accordance with the invention.Thus, for example, a mixture of gammaand delta-tocopherols separated asa concentrate from soybean oil and having an Emmerie-Engel value of59.7% and is treated by dissolving 10.4 grams of the mixed concentratein 29 cc. of isobutyl alcohol containing 2.25 g. of formaldehyde, 7.5 g.of dimethylamine hydrochloride and 1.1 ml. of concentrated hydrochloricacid. The reaction mixture is reiiuxed for 3 hours, and the resultingaddition product extracted with ether, washed to neutrality andcatalytically reduced to alpha-tocopherol having a vitamin E biologicalpotency much higher than the original concentrate,

In the aminoalkylation of beta-, gamma-, or delta-tocopherolrespectively, the aminoalkylation occurs in the 7 position ofbeta-tocopherol, the 5 position of gamma-tocopherol and the'5 and 7positions of delta-tocopherol and the substituent group is thereafterreduced to the corresponding alkyl group preferably by catalytichydrogenation or by treatment with an anhydride such as acetic anhydridecausing cleavage of the carbon to nitrogen bond followed byhydrogenation or by other suitable reduction reaction.

Reduction of the aminomethylated tocopherol material results in recoveryof the original amine. Thus when beta-, gamma-, or deltatocopherol istreated with an aldehyde having the formula RCHO where R is eitherhydrogen or a hydrocarbon group such as an alkyl group, an aryl group oran aralkyl group, and with an aminating agent having the formula R'R."NHwhere R and B respectively are either hydrogen or a hydrocarbon groupsuch as an alkyl group, an aryl group or an aralkyl group, the resultingsubstituent group introduced in the position of an aromatic hydrogenatom on the tocopherol nucleus has the formula R'RXNRP. Thus, forexample, when gamma-tocopherol is reacted with formaldehyde and anaminating agent such as dimethylamine, the substituent group in the 5position of the gamma-tocopherol is (CH2)2NCH2-; with ammonia, thesubstituent group is NH CI-Iz; and with ethylamine, the substituentgroup is CzHsNH-CHain the 5 position. The aminomethylatedgammatocopherol is then reduced to the methylated product,alpha-tocopherol.

Typical examples of the conversion of tocopherol compounds of relativelylow potency to the corresponding alpha-tocopherol compounds are asfollows:

Example 1 A pure preparation of natural beta-tocopherol (0.65 g., 100%by Emmerie-Engel assay) was dissolved in ether (25 co.) in athree-necked flask equipped with a stirrer. While the temperature of thesolution was kept at 30 by a water bath, 5 cc. of concentratedhydrochloric acid and 0.4 cc. of aqueous 40% Formalin was added andhydrogen chloride gas bubbled through the mixture for 25 minutes. Themixture was reduced by the cautious addition of 1.0 g. of zinc dust overa period of 30 minutes The reaction mixture was worked up by addingwater and washing the ether solution four times with water to removezinc chloride ,and

6. acid, and then filtered through Doucil (10 g? to remove thelasttraces of zinc chloride. Removal of the solvent left a light yellowoil (070 g.) which had an Emmerie-Engel potency of 76%.

Proof of structure.-In order to prove the synthesis of alpha-tocopherol,the acid succinate ester which has been previously characterized (J. A.C. S. 65, 922 (1943)), was prepared and isolated in the followingmanner:

The concentrate was esterifiecl by heating it at in pyridine (3 cc.)with succinic anhydride (1. g.) for 4 hours. The reaction mixture wasthen poured on a mixture of ice and 5% aqueous hydrochloric acid andextracted with ether. After washing with 5% acid and water the solutionwas dried and the solvent distilled, leaving 0.85 g. of crude acidsuccinate.

Further purification was accomplished by solution of the crude succinatein ethylalcohol (20 cc.) and neutralization with 10% alcoholic KOH,litmus being used as an outside indicator. The alcohol solution wasadjusted to 83% by the addition of water and the solution then extractedwith petroleum ether (Skellysolve F) saturated with 83% ethyl alcohol.Under these conditions the tocopherol acid succinate remained in thealcohol solution While the non-acidic materials were extracted in thepetroleum ether. After acidification of the alcohol extract thetocopherol acid succinate was extracted with ether and recovered to give0.64 g. of purified product.

Crystallization was accomplished by dissolving the ester in SkellysolveF (8 cc.) and cooling the solution to 0. The white solid which separatedwas recrystallized at room temperature from petroleum ether and meltedat 7677 (0.48 g.), which is the melting point of alphatocopherolsuccinate. A mixed melting point determination showed no depression. Theabsorption maximum and extinction coefficient of the synthesizedpreparation were also identical with that of alpha-tocopherol acidsuccinate.

Example 2 ature and the mixture allowed to stand over-' night. Themixture was washed with water, dried and evaporated under vacuum. Theresulting oil assayed for 46% tocopherol and gave a positive chloridetest after a sodium fusion. It was then reduced with zinc-mercuryamalgam and concentrated hydrochloric acid in ethanol and then Vacuumdistilled after separation from the reaction mixture. Two distillatefractions were obtained which contained 22.5% of the originaltocopherol. A portion of the second distillate was treated with succinicanhydride and pyridine and 0.1 g. of alpha-tocopherol acid succinate wasisolated and identified in the mane ner described in Example 1.

Example 3 To a solution of 0.5 g. of amma-tocopherol concentrate (62.5%by Emmerie-Engel assay, approximately 10% alpha-, 60% gamma-, and 30%delta-tocopherol by chemical assay, concentrated from a commercialvitamin E concentrate by chromatography) in 20 cc. of ether, 1 cc. ofaqueous Formalin and cc. of concentrated hydrochloric acid were added.The mixture was vigorously stirred and hydrogen chloride gas introducedfor thirty minutes at room temperature. The reaction was worked up asabove and the resulting oil reduced. The final product assayed 55.4%tocopherol and when succinated, 0.13 g. of alpha-tocopherol acidsuccinate was isolated and identified; yield, 34%.

Example 4 A solution of 0.667 g. of pure gamma-tocopherol (originallyisolated from soybean oil) was treated as in Example 3. As a finalproduct 0.2 g. of pure alpha-tocopherol acid succinate was isolated andidentified; yield, 24.2%. A biochemical assay of the succinate by theEvans resorption test indicated that it was as active in preventingsterility as pure alpha-tocopherol using alpha-tocopherol acetate as thestandard. In Examples 3 and 4, the conversion is undoubtedly better thanthe yields indicate, since it is diflicult to succinate and crystallizequantitatively.

Example 5 An ethereal solution of 3.35 g. of gamma-tocopherolconcentrate (62% by Emmerie-Engel assay) was treated with 2 cc. ofchlormethyl ether under reflux for 1 hours. The ethers were removedunder nitrogen and the resulting oil reduced and distilled in a smallpot still. A distillate was obtained which weighed 1.4 g. and assayed50% tocopherol. The oil was found to contain 87% alpha-tocopherol bychemical assay and 72% by biological assay using naturalalpha-tocopherol acetate as the standard,

xample 6 A 20% ether solution of 45 g. of tocopherol concentrate (33%total tocopherols by Emmeric- Engel assay consisting of approximatelyalpha-, 60% gamma-, and 30% delta-tocopherol by chemical assay)concentrated from soybean oil by molecular distillation was treated with30 cc. of concentrated hydrochloric acid and 6 cc. of aqueous Formalinand stirred vigorously for 130 minutes. At the end of this time, 10 g.of zinc powder was slowly added directly to the reaction mixture andreduction allowed to procecd for 30 minutes. The ether layer was thenseparated, washed, dried and evaporated to yield a light yellow oil(45.1 g.) with an Emmeric- Engel potency of 32.4%. Moleculardistillation of the oil gave a recovery of 83.5% of material whichdistilled in the vitamin E range and which assayed chemically for 37.6%gama-tocopherol and 62.4% alpha-tocopherol.

Example 7 A substantially pure preparation of deltastocopherol (0.83 g.,99.5% by Emmerie-Engel assay) was dissolved in ethyl ether (31 cc.) in athree-necked flask equipped with a stirrer. While the temperature of thesolution was kept at 30 by a water bath, hydrogen chloride gas wasbubbled through the solution for 5 minutes from a cylinder, then equeousHC1 (6.2 cc) .was add- 8 ed together with 35% Formalin solution (5 cc.).The mixture was stirred for minutes with HCl gas passing through. A teston a sample. of the solution then indicated that chloromethylation wasvirtually complete (as determined by loss of ability to couple withdiazotized dianisidine to give a red color).

The chloromethyl compound was then reduced with zinc dust (2 g.) bystirring at room temperature for minutes. The ether solution was washedfour times with water to remove zinc salts and filtered through Doucil(12 g.) to re{ Example 8 10 g. of soybean tocopherol concentrate (58.7%potency by Emmerie-Engel assay, 95% gammatocopherol by chemical assay)was dissolved in '75 cc. of ether and 1.0 g. of acetaldehyde added.Under stirring, HCl gas was bubbled through the mixture at roomtemperature for 1 /2 hours. The chloroethylated compound was reduced byadding 16.5 g. of a 10% Zn-amalgam' over a period of /2 hour andstirring the mixture for an additional hour. The mixture was extractedwith ether, washed with water to neutrality, and dried over sodiumsulfate. Evaporation of the ether gave a light brown oil, (38% potencyby E-E, 75% 5-ethyl--7,8 dimethyl tocol by chemical analysis)representin a yield of 49%. This material was concentrated by moleculardistillation and distilled at 140-180" C. at 7 microns.

Example 9 200 g. of a soybean tocopherol concentrate (50% combinedtocopherols by the Emmeric- Engel assay, approximately 10% alpha-, 60%gamma-, and delta-tocopherol by chemical assay) was treated with 104 g.of acetic anhyclride and g. of pyridine and heated for one hour on thesteam bath. The reaction mixture was dissolved in 2 liters of ether,washed three times with 5% 1101, three times with water, and dried oversodium sulfate. Evaporation of the solvent gave 109 g, of tocopherolacetate concenra e. 1

40 g. of the above prepared concentrate was placed in a three-neck roundbottomed flask equipped with a mechanical stirrer. To the oil cc. ofFormalin and cc. of concentrated hydrochloric acid was added. While thetemperature of the reaction mixture was kept at 80 C., hydrogen chloridegas was passed through the mixture with stirring for three hours. Theoil was then extracted with ether, worked free of acid, and dried oversodium sulfate. Evaporation of the solvent under vacuum left a light redoil (43 g.). l/Vhen a sample was treated with alkali, a copious test forchloride ion was obtained indicating the introduction of thechloromethyl group.

The chloromethylated oil was dissolved in 300 00.01 ether and treatedwith 60 cc. of concentrated hydrochloric acid and 25 g. of zinc dust forone hour. Separation of the reduced product gave 40.5 g. of a lightyellow oil which was identified as an alpha-tocopherol acetateconcentrate by saponification to the free tocopherol followed bysuccination and isolation of alphatocopherol succinate as in Example 1.

Example 10 0.5 g. of pure gamma-tocopherol in cc. of absolute alcoholwas treated with 0.1 g. piperidine, 0.1 g. paraformaldehyde and 3 dropsof concentrated hydrochloric acid. The resulting mixture was heatedunder reflux for two hours. Separation of the oil from the mixtureproduced a light brown pasty mass (0.55 g.). A coupling determinationusing diazotized dianisidine showed that a reaction had occurred. atposition 5.

This product was hydrogenated at 2000 lbs. pressure over copper chromitecatalyst in alcohol as a solvent for three hours. Chemical testsindicated that piperidine had been regenerated. The reduced product wasisolated and succinated with succinic anhydride in pyridine. From thesuccinated mixture 0.1 g. of alpha-tocopherol succinate was isolated asin the previously described examples.

Example 11 To a solution of 18.2 g. of tocopherol concentrate (55% byEmmerie-Engel assay, approximately alpha-, 30% delta-, 60%gam1natocopherol) in 182 cc. of isopropyl ethe, 2.80 cc. of benzaldehydewas added and the mixture stirred vigorously while hydrogen chloride gaswas bubbled through the solution for one hour. The temperature of thereaction was regulated at 38 C. by a water bath.

The reaction mixture was then reduced by the addition of g. of zinc dustover a period of 1 /4 hours at C. The oil was separated as an etherextract by the addition of water, the ether extract washed three timeswith water, and passed through a column of Doucil for finalpurification. Evaporation of the solvent left a light red oil (20.45 g.,42.4% E-E potency, 87% yields). An analysis by coupling withO-dianisidine showed that only 9% of the potency was due to gammaanddelta-tocopherols.

The oil was distilled in a molecular still and a distillate obtained(potenc in overall yield of 78.5%. The distillate was a light yellowviscous oil which distilled at 180 at *7 microns. I

It analyzed for 6% gamma and delta-tocopherol.

This application is a continuation in part of copending application,Serial No. 684,769 filed July 19, 1946, now U. S. Patent 2, i86,539,which in turn was a continuation in part of application Serial No.589,927 filed April 23, 1945, now abandoned.

What I claim is:

1. The method of treating a tocopherol compound having at least onearomatic hydrogen atom on the nucleus and being selected from the classconsisting of beta-tocopherol, gammatocopherol and delta-tocopherolwhich comprises reacting said tocopherol compound with an al dehyde andan aminating agent selected from the class consisting of ammonia,primary amines, secondary amines, and salts thereof and therebyreplacing said aromatic hydrogen atom with an aminohydrocarbon group,and thereafter re- 10 ducing said aminohydrocarbon group to thecorresponding hydrocarbon group.

2. The method which comprises subjecting a tocopherol compound having atleast one aromatic hydrogen atom on the nucleus and being selected fromthe class consisting of beta-tocopherol, gamma-tocopherol anddelta-tocopherol to aminoalkylation and reduction and thereby'r eplacingsaid aromatic hydrogen atom with an alkyl group.

3. The method of enhancing the vitamin E biological potency of atocopherol compound having at least one aromatic hydrogen atom on thenucleus and being selected from the class consisting of beta-tocopherol,gamma-tocopherol and delta-tocopherol which comprises replacing saidaromatic hydrogen atom with a methyl group by subjecting said tocopherolcompound to aminomethylaticn and reduction.

4. The method of enhancing the vitamin E biological activity ofbeta-tocopherol which coinprises replacing the aromatic hydrogen atom inthe 7 position of said beta-tocopherol by subjecting saidbeta-tocopherol to aminomethylation and reduction.

5. The method of enhancin the vitamin E bi ologica-l activity ofgamma-tocopherol which comprises replacing the aromatic hydrogen atom inthe 5 position of said gamma-tocopherol by subjecting saidgamma-tocopherol to aminomethylation and reduction.

6. In the method of enhancing the vitamin E biological activity ofdelta-tocopherol by introducing methyl groups into the 5 and '7positions of said delta-tocopherol, the steps which comprise introducina methyl group into at least one of said positions by subjecting saiddelta-tocopherol to aminomethylation and reduction.

7. The method of enhancing the vitamin E biological potency ofbeta-toc0pheral which comprises introducing a methyl group into the 7position of said beta-tocopherol by aminomethylating said tocopherol andreducing the resulting aminomethylated tocopherol, saidaminome-thylating being effected by reacting said beta-tocopherolsimultaneously with a compound of the formula (CI-M wherein n is a wholeinteger, and an aminating material selected from the class consisting ofammonia, primary amines, secondary amines, and salts of said materials.

8. The method of enhancing the vitamin E biological activity ofgamma-tocopherol which comprises introducing a methyl group into the 5position of said gamma-tocopherol by subjecting said gamma-tocopherol toaminomethylation and reduction, said aminomethylation being effected byreacting said beta-tocopherol simultaneusly with a compound of theformula (CH20)n wherein n is a whole integer, and an aminating materialselected from the class consisting of ammonia, primary amines, secondaryamines, and salts or" said materials.

9. The method of treating delta-tocopherol having aromatic hydrogenatoms in the 5 and 7 positions on the nucleus which comprisesintroducing a methyl group into at least one of said positions byaminomethylating and reducing said delta-tocopherol, saidaminomethylating being effected by simultaneously reacting saiddelta-tocopherol with a compound of the formula (CHzO) n wherein n is awhole integer, and an aminating material selected from the classconsisting of ammonia, primary amines, secondary amines, and salts ofsaid materials.

10. The method of enhancing the vitamin E biological activity ofdelta-tocopherol which comprises introducing methyl groups into the and7 positions on the nucleus of said deltatocopherol by aminomethylatingand reducing said delta-tocopherol, said aminomethylating bein effectedby simultaneously reacting deltatocopherol with a compound of theformula (CI-I) wherein n is a whole integer, and an aminatin materialselected from the class consisting of ammonia, primary amines, secondaryamines, and salts of said materials.

11. As a new chemical compound, a substituted tocopherol selected fromthe class consisting of beta-tocopherol, gamma-tocopherol anddeltatocopherol having at least one nuclear substituent group in theposition normally occupied by an aromatic hydrogen atom, saidsubstituent group having the formula XR wherein R is a hydrocarbonradical and X is a member selected from the class consisting of aminogroups P and hydrocarbon-substituted amino groups.

12. As a new chemical compound, gamma-tocopherol having a substituentgroup in the 5 position thereof consisting of an alkyl radical J'Qinedrespectively to the nuclear carbon atom in the 5 position of saidgamma-tocopherol and to a nitrogen atom of an amino radical selectedfrom the class consisting of amino groups and hydrocarbon-substitutedamino groups.

13. As a new chemical compound, beta-tocopherol having a substituentgroup in the '7 position thereof consisting of an alkyl radical Joinedrespectively to the nuclear carbon atom in the 7 position of saidbeta-tocopherol and. to a nitrogen atom of an amino radical selectedfrom the class consistin of amino groups and hydrocarbon-substitutedamino groups.

14. As a new chemical compound, delta-tocopherol having substituentgroups in the 5 and 7 positions thereof each consisting of an alkylradical joined respectively to the nuclear carbon atom in the 5 and 7positions of aid deltatocopherol and to a nitrogen atom of an aminoradical selected from the class consisting of amino groups andhydrocarbon-substituted amino groups.

15. As a new chemical compound, gamma-tocopherol having a substituentCI-I2X group in the 5 position thereof, in which substituent 12 group Xis a member selected from the class consisting of amino groups andhydrocarbon-substituted amino groups, said new compound havin theformula 16. As a new chemical compound, beta-tocopherol having asubstituent --CH2X group in the 7 position thereof, in which substituentgroup X is a member selected from the class consisting of amino groupsand hydrocarbon-substituted amino groups, said new compound having theformula LEONARD VIEISLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Organic Reactions, vol. N. Y., 1942.

1, page 311, Wiley

11. AS A NEW CHEMICAL COMPOUND, A SUBSTITUTED TOCOPHEROL SELECTED FROMTHE CLASS CONSISTING OF BETA-TOCOPHEROL, GAMMA-TOCOPHEROL ANDDELTATOCOPHEROL HAVING AT LEAST ONE NUCLEAR SUBSTITUENT GROUP IN THEPOSITION NORMALLY OCCUPIED BY AN AROMATIC HYDROGEN ATOM, SAID SUBSTITUTEGROUP HAVING THE FORMULA XR- WHEREIN R IS A HYDROCARBON RADICAL AND X ISA MEMBER SELECTED FROM THE CLASS CONSISTING OF AMINO GROUPS ANDHYDROCARBON-SUBSTITUTED AMINO GROUPS.